Note that pathology predicted response to the combination therapy, as 14 of 15 patients with clinical benefit had endometrioid tumors.

MILAN -- Half of patients with recurrent endometrial cancer benefited from treatment with hormonal therapy plus an mTOR inhibitor, results of a small clinical trial showed.

In the subgroup of patients with endometrioid tumors, two-thirds had objective responses or stable disease with the combination of letrozole (Femara) and everolimus (Afinitor).

"The combination of everolimus and letrozole showed an encouraging clinical benefit rate (CBR) in pretreated patients with recurrent endometrial cancer," Brian Slomovitz, MD, of Atlantic Health System in Morristown, N.J., said here at the European Society of Gynecological Oncology. "The combination was well tolerated in this cohort of patients."

"Future studies are needed to better evaluate the role of mTOR inhibition in overcoming hormonal resistance," he added.

Options for systemic therapy in recurrent endometrial cancer include multiple hormonal and cytotoxic agents, according to National Comprehensive Cancer Network guidelines. But the guidelines do not recommend any targeted therapies, emphasizing the need to examine new approaches, Slomovitz said.

The biology of endometrial carcinoma suggests that drugs in the mammalian target of rapamycin (mTOR) inhibitor class might have a role in systemic treatment of the cancer.

As many as 60% of endometrial cancers have mutations in the tumor suppressor gene PTEN. Studies of PTEN knockout mice have shown that 100% of the animals develop endometrial hyperplasia and 40% develop endometrial carcinoma, Slomovitz continued.

Loss of PTEN activates mTOR, promoting cell-cycle transit, angiogenesis, and nutrient uptake, all of which are essential to tumor development and progression.

Pathology studies have shown that mTOR and S6 kinase (S6K) are overexpressed in primary and recurrent endometrial cancer, Slomovitz said.

Use of hormonal therapy in endometrial cancer dates back more than 60 years. Estrogen receptor function in endometrial cancer is mediated in part by MAPK signaling, and mTOR inhibition has been shown to disrupt growth processes in estrogen-sensitive tumors.

Given that background, Slomovitz and colleagues in New Jersey and at MD Anderson Cancer Center in Houston hypothesized that the combination of an aromatase inhibitor and an mTOR inhibitor would have activity against endometrial cancer.

To test the hypothesis, investigators enrolled 41 patients with advanced or recurrent endometrial cancer and a treatment history of no more than two prior systemic regimens.

All patients received oral everolimus and oral letrozole daily until progression or development of unacceptable toxicity. Response was assessed after completion of two 28-day cycles of treatment, followed by confirmatory assessments after every three cycles.

The trial had a statistical endpoint of a 20% clinical benefit rate.

The patients received a total of 145 cycles of the combination therapy. Slomovitz said 30 patients were available for response and 37 for toxicity.

Overall, 15 of 30 patients achieved a clinical benefit, consisting of four complete responses, two partial responses, and stable disease in nine patients. Patients who achieved clinical benefit received an average of 7.5 cycles of therapy and a median of eight cycles.

Ten of the 15 patients remain on treatment, three patients completed therapy and entered observation, and two patients had progressive disease.

The most common adverse events, irrespective of grade, were fatigue (39%), stomatitis (35%), nausea (29%), anorexia (16%), and vomiting (13%). The most common grade 3 adverse event was fatigue (10%).

Hyperglycemia, hypertriglyceridemia, and anemia each occurred in 19% of patients, neutropenia in 16%, and hypercholesterolemia and thrombocytopenia each in 13%. The most common grade 3 laboratory adverse event was thrombocytopenia, occurring in 6% of patients.

Pathology results showed that 22 (74%) patients had endometrioid tumors and 26% had pure serous or mixed histology. Half of the patients had stage I/II disease and the rest had grade III/IV. Additionally, 51% of patients were estrogen receptor positive, 14% were negative, and 35% had unknown status.

Pathology predicted response to the combination therapy, as 14 of 15 patients with clinical benefit had endometrioid tumors. All six patients who had complete or partial responses also had endometrioid tumors. One patient with a serous tumor had stable disease.

The study was supported by Novartis.

Slomovitz and co-investigator Robert L. Coleman have disclosed relationships with Novartis.

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